Intracerebral hemorrhage (ICH) is the stroke subtype with the highest death rate and poorest prognosis in survivors. Presently, there are no effective treatments. The cellular and molecular mechanisms through which intracerebral blood induces injury are not well understood. Previous findings by ourselves and others suggest that both rapidly initiated and delayed oxidative stress and inflammatory responses likely contribute to vasogenic edema, tissue injury and morbidity after ICH. Considerable evidence suggests that red cell lysis with release of hemoglobin containing iron contributes to tissue injury following ICH. In this regard, recent findings demonstrate the effectiveness of iron chelation with deferoxamine in improving outcome following ICH. Additionally, we previously demonstrated that early surgical hematoma removal in our lobar ICH model markedly reduced perihematomal edema and protected the blood-brain-barrier (BBB). Thus, based on these findings, we will test the overall hypothesis that combining iron chelation therapy with surgical clot removal for ICH treatment will significantly reduce white matter injury following ICH. Specifically, molecular events activated by red blood cell lysis and hemoglobin/iron release in white matter microglia and/or astroglia will be markedly suppressed. As a consequence, combined treatment will attenuate these molecular responses and will protect white matter by reducing demyelination, axonal injury, gliosis and cavitation. Based on our published and preliminary data, this protection will occur through mechanisms that include reductions in oxidative stress and pro-inflammatory cytokine upregulation. We will employ a well-characterized, clinically relevant, large animal (pig) ICH model. The pig brain has significant white matter and its size facilitates clot removal studies. We propose to define the effectiveness of iron chelation therapy and surgical clot removal alone and in combination. We will also test the efficacy of Exjade, an iron chelator that can be administered orally. In Aim #1, we will examine the temporal course of our proposed treatments on neuropathologic outcomes. In Aim #2, we will examine the mechanisms of these treatments, specifically, their ability to interrupt early and delayed oxidative stress and proinflammatory cytokine and target gene and protein expression in perihematomal brain tissue. To accomplish these Aims we will use standard histological, immunocytochemical, molecular and biochemical methods. We expect that successful completion of these proposed studies will demonstrate that iron chelation therapy and surgical clot removal can improve white matter outcome following ICH. Furthermore, these studies should provide a better understanding of the early and delayed mechanisms underlying brain injury from ICH. PUBLIC HEALTH RELEVANCE: Project Narrative: ICH is a devastating type of stroke with high death and disability rates. Currently there are no drug treatments for ICH patients and surgical treatment is controversial. This proposal's overall goals are to determine the reasons why bleeds into brain cause damage and to examine the effectiveness of new drug and surgical therapies to reduce or prevent injury and improve outcome.